Efficacy of antithrombin III in endotoxin-induced disseminated intravascular coagulation

Antithrombin III (AT III) is a major modulator of the clotting cascade and is decreased in disseminated intravascular coagulation (DIC). AT III was given as a pretreatment to dogs with endotoxin-induced DIC. Significant improvement in clotting parameters (prothrombin time, fibrinogen, fibrin degradation products) was noted. There was no effect on platelets. Mean arterial blood pressure was improved, while there were no other significant changes in other measured hemodynamic, acid-base, or biochemical variables. It was concluded that AT III was effective in ameliorating endotoxin-induced changes in the clotting profile. AT III may prove to be a beneficial therapy in acquired DIC.     

Abnormal antithrombin III (antithrombin III "Budapest") as a cause of a familial thrombophilia

A family with a high incidence of spontaneous thromboembolism has been investigated and those members affected were found to have significantly depressed levels of plasma and serum heparin cofactor activity; i.e., antithrombin III and anti-Xa activity. Further studies revealed that despite a marked diminution of antithrombin III activity in these patients measurement of antithrombin III by immunological techniques showed the levels to be normal. It is concluded that this anomaly represents a defect in the synthesis of the antithrombin III molecule. The abnormality appeared to be inherited but the mode of inheritance could not be determined with the available data.     

Influence of antithrombin III on coagulation and inflammation in porcine septic shock.

The physiological inhibitor of thrombin, antithrombin III (ATIII, Kybernin P) was investigated for its antiinflammatory and anticoagulant effects in a pig model of septic shock. Pigs were infused with a dose of 0.25 microgram. kg-1. h-1 of lipopolysaccharide (LPS) over a period of 3 hours. Animals developed systemic inflammation, disseminated intravascular coagulation (DIC), organ failure and cardiovascular abnormalities, namely pulmonary hypertension and systemic hypotension. Twenty septic pigs were allocated to 2 study groups, treated either with ATIII (n=10) or placebo (n=10). ATIII was administered as a 250-U/kg IV bolus infusion for 30 minutes (-60 to -30 minutes) followed by a single IV bolus of 125 U/kg (t=0) and a second 30-minute infusion of 250 U/kg (120 to 150 minutes). ATIII significantly prevented the development of a DIC; the increase in fibrin monomers (placebo, 11.4+/-9.1 reciprocal titers, at 6 hours) was completely overcome by ATIII (P<0. 05). ATIII significantly prevented the increase in thromboxane (TXB2) levels, which were 809+/-287 pg/mL in the placebo and 420+/-174 pg/mL in the verum group after 6 hours (P<0.02). On the other hand, ATIII had no influence on TNF levels. In a lethal study with an increased dose of LPS (0.5 microgram. kg-1. h-1). A significant reduction in mortality was observed in the ATIII group (0 of 7) compared with the placebo group (4 of 6) (P<0.05, chi2 test) a significant reduction of pulmonary hypertension (placebo, 42.0+/-11. 1 mm Hg; ATIII, 23.6+/-7.5 mm Hg, P<0.05), but no effect on systemic hypotension, was noted in the ATIII group. It was thus concluded that modulation of the procoagulatory state by substitution of ATIII results in a late beneficial antiinflammatory effect in this model of septic shock.     

Management with antithrombin III concentrate in a pregnant woman with hereditary antithrombin III deficiency

Pregnant women with hereditary antithrombin III (AT-III) deficiency are frequently associated with thromboembolic disorders. We have treated a pregnant woman with hereditary AT-III deficiency, who had suffered from thromboembolic disorders at her past three gestations, with AT-III concentrate. Dosage of AT-III concentrate to maintain plasma AT-III activity over 80% was 3,500 units per week during second and third trimesters, but more frequent administration was necessary around delivery. In recent reports, pregnant women with hereditary AT-III deficiency had been treated with heparin or warfarin except for during abortion and delivery, in which time AT-III concentrate was widely utilized. But the use of heparin or warfarin during gestation is occasionally harmful, AT-III concentrate should be chosen for management in pregnancy in women with hereditary AT-III deficiency.     

Liver dysfunction rather than intravascular coagulation as the main cause of low protein C and antithrombin III in acute leukemia

Protein C, a newly identified inhibitor of blood coagulation, was measured immunologically in 58 patients with untreated acute leukemias and compared with that of normal subjects. On the average, slightly lower values were found. However, the 17 patients with overt laboratory pictures of decompensated disseminated intravascular coagulation (DIC), including 11 cases with acute promyelocytic leukemia, had protein C concentrations no lower than those of the remaining 41 patients without DIC. Antithrombin III activity and antigen were normal and, like protein C, not lowered in DIC. The concentrations of both proteins were closely correlated with changes in the indexes for liver synthetic function. A subgroup of 13 patients with hyperleukocytic leukemias had lower protein C and antithrombin III, in line with the more compromised synthetic function of their livers. Our findings indicate that liver impairment rather than DIC is the main cause of the changes in the two naturally occurring inhibitors of blood coagulation.     

Prophylactic use of antithrombin III concentrate following surgery in congenital antithrombin III deficiency

Antithrombin III is the major physiological inhibitor of thrombin, and congenital deficiency of antithrombin III is associated with increased risk of venous thrombosis either spontaneously or following trauma, surgery or pregnancy. The successful use of antithrombin III concentrate during and following surgery to prevent venous thrombosis is described in a previously asymptomatic man with familial antithrombin III deficiency.     

Intravascular coagulation in acute liver failure in rats and its treatment with antithrombin III.

Liver damage was induced in rats by injection of dimethylnitrosamine (DMN) or carbon tetrachloride (CCl4). Fibrin clots were observed in the hepatic sinusoids at 12 hours and soluble fibrin monomer complexes were markedly detected at 24 hours only in the rats given DMN. When antithrombin III concentrate was infused at 12 hours there was a dose dependent improvement of the values of serum total bilirubin, SGPT, prothrombin time, peripheral platelet count, and plasma fibrinogen and coagulation factor VIIIC and of the histological degree of liver injury at 24 hours in the DMN group. The CCl4-group showed no such improvement. Intravascular coagulation may complicate the course of certain types of acute liver injury and contribute to its aggravation in rats. Under such circumstances, treatment with antithrombin III concentrate would be beneficial.     

Hypercoagulability during l-asparaginase treatment: the effect of antithrombin III supplementation in vivo

To evaluate the occurrence of hypercoagulability during treatment with L-asparaginase (L-ase), thrombin-antithrombin complex (TAT) and D-dimer levels in plasma were serially measured in 15 consecutive adult patients with acute lymphoblastic leukaemia or lymphoblastic lymphoma who had recently completed a chemotherapy cycle with cytosine arabinoside and methotrexate. The first eight patients (group A) received i.v. L-ase alone (20,000 U/m2 on alternate days over 10 d); the last seven patients (group B) received, in addition to L-ase, bolus injection of antithrombin concentrate (2000 U) on alternate days for a total of six administrations, beginning with the second L-ase infusion. Increased levels of TAT (P less than 0.05) and D-dimer (P less than 0.01) were observed prior to L-ase, possibly related to inflammation and cytolysis secondary to previous chemotherapy. In patients treated with L-ase alone, further elevation of TAT (P less than 0.05) and persistence of increased D-dimer were observed, associated with marked reduction of the anticoagulant activities of protein C, protein S and antithrombin III. At variance, in patients receiving antithrombin III supplementation there was no increase of TAT and a normalization of D-dimer levels occurred during L-ase treatment. In these patients, mean plasma antithrombin III activity was maintained at levels higher than 70% of normal throughout the treatment. The rate of decline of fibrinogen, factor IX, protein C and protein S was unaffected by antithrombin III supplementation, indicating that hypercoagulability has little if any relevance for the reduction of coagulation factors and inhibitors induced by L-ase treatment. The usefulness of antithrombin III concentrates in preventing thromboembolic complications in patients submitted to L-ase treatment remains to be determined.     

Treatment of venous thrombosis in antithrombin III deficient patients with concentrates of antithrombin III

Summary Two patients with familial antithrombin III deficiency developed deep venous thrombosis of the lower limb. The diagnosis of venous thrombosis was made by the indium labelled platelet technique which also allowed for the daily assessment of thrombus size. Each patient received treatment with Warfarin, subcutaneous heparin, and infusions of antithrombin III concentrates. The authors conclude that infusions of antithrombin III concentrates may be of value in limiting the extent of acute thrombosis in patients with a severe deficiency of this protein and may help prevent pulmonary embolism. The haemorrhagic risk of continuing modest doses of heparin with high dose ATIII therapy appears small. In addition to its value in the diagnosis of venous thrombosis the indium platelet technique may give an early indication of thrombus extension and may thus indicate the effectiveness of treatment.     

Treatment of venous thrombosis in antithrombin III deficient patients with concentrates of antithrombin III

Summary Two patients with familial antithrombin III deficiency developed deep venous thrombosis of the lower limb. The diagnosis of venous thrombosis was made by the indium labelled platelet technique which also allowed for the daily assessment of thrombus size. Each patient received treatment with Warfarin, subcutaneous heparin, and infusions of antithrombin III concentrates. The authors conclude that infusions of antithrombin III concentrates may be of value in limiting the extent of acute thrombosis in patients with a severe deficiency of this protein and may help prevent pulmonary embolism. The haemorrhagic risk of continuing modest doses of heparin with high dose ATIII therapy appears small. In addition to its value in the diagnosis of venous thrombosis the indium platelet technique may give an early indication of thrombus extension and may thus indicate the effectiveness of treatment.     

Clinical and genetic aspects of antithrombin III deficiency and abnormal antithrombin III

Antithrombin III (AT III) has been confirmed to play an important role as a serine protease inhibitor in the mechanism of blood coagulation, and its deficiency or abnormality is found to cause thromboembolic disorders by reducing the anticoagulant activity. In this paper AT III gene of patient with congenital AT III deficiency, which was suggested to have qualitative abnormality by isoelectric focusing, was investigated. Analysis of the genomic structure by Southern blot hybridization with a cDNA probe (pAT6) revealed no detectable changes indicating any deletions, rearrangements and translocations. Therefore, we focused to analyze the sequence of exon 6 of AT III gene by polymerase chain reaction (PCR) methods followed by direct sequencing analysis. Nucleotide sequencing of exon 6 of AT III gene showed a G to T transitional mutation resulting in the conversion of arginine-406 to methionine coexisted with normal allele which encodes arginine. The mutation is located near the reactive center of AT III molecule, which region has been proved to be highly conserved during the evolution of serine protease inhibitor (serpin) family. From these results, it is concluded that the new type of mutation at amino acid site 407, which is similar to AT III Utah, is important for maintaining the structural and biological function of this inhibitor.     

Activities of antithrombin III and heparin cofactor II in patients with pathologic blood coagulation conditions]

To investigate the physio-pathological functions of HC-II, assays for HC-II and AT-III were performed simultaneously on the samples from patients with DIC, liver dysfunction or renal disease from the three view points of consumption, production and loss of AT-III and HC-II. For the AT-III activity, two kinds of assays were applied: the automatic chromogenic substrate method and a newly developed clotting method which receives no effects from HC-II activity. The activity of HC-II was significantly lower than that of AT-III in patients with either DIC or liver dysfunction. However, no significant difference between HC-II and AT-III activities in patients with either thrombosis or renal disease. There were high correlations between HC-II and AT-III activities were found in the patients with liver dysfunction, suggesting that low activity was due to decreased production of HC-II and AT-III in the liver. It will be necessary that elucidation of the significant functions of HC-II not only in coagulation and hemostasis but also in regulation of local inflammation and invasion of neoplasm is necessary.     

Relevance of antithrombin III in thrombogenesis: the diagnosis and therapy of antithrombin III defects

Pathological and inconspicuous AT III measuring values were compared with the clinical findings (arterial occlusive diseases, postthrombotic syndromes, acute profound thrombosis of the pelvic veins and the leg veins, acute heparin tolerance in several basic diseases). After calculatory elaboration of all rightly positive and falsely positive, rightly negative and falsely negative laboratory results becomes evident that the positive power of prognosis of the AT III determination is unsatisfactory for a certain basic disease and the negative evidence in these questionings rather well satisfy for the functional measuring method. - The sensitivity of the functional AT III test for the recognition of increased heparin tolerances is quite satisfactory, and the test for the answer of this questioning also suitable and more sensitive than the immunological proof method. - The high percentage of rightly positive and rightly negative findings of all tested results of apparently healthy persons and the groups of patients represented makes clear, which role plays the AT III as a physiologic inhibitor against coagulation-active serine proteases particularly in DIC and in profound thrombosis of the pelvic and leg veins. - For the observation of the course in profound thrombosis of the pelvic and led veins, features of postthrombotic condition and the DIC at least the functional determination of AT III is decisively important.     

Hereditary antithrombin III deficiency: Effect of antithrombin III deficiency on platelet function

Antithrombin III (AT III) is the main physiologic inhibitor of thrombin, and activated factors X and IX as well. Normal levels of AT III appear to be necessary to maintain blood fluidity and to prevent thrombosis. Four families with AT III deficiency and recurrent venous thromboembolism have been reported on. We present an additional family with AT III deficiency and a high incidence of thromboembolism. AT III levels were determined by both a functional and an immunologic assay. Results of platelet function tests, not previously reported in persons with AT III deficiency, were found to be normal. Following gel filtration, the platelets were very sensitive to thrombin. Thrombin-induced platelet aggregation appears to be dependent on a balance between the amount of thrombin and AT III present.     

Familial deficiency of antithrombin III

The systematic search for a deficiency in antithrombin III must be considered in case of: venous thrombosis in a young patient, recurrent venous thrombosis especially if these occurred under Heparin, venous mesenteric infarction since this type of thrombosis is rare and seems relatively frequent in case of congenital deficiency in antithrombin III, familial past history of venous thrombosis in a woman desiring to undergo estrogen-progesterone therapy. The most often used techniques are: study of antithrombin III activity by amidolytic method and titration by immunodiffusion. Anti-vitamin K treatment is the only effective therapy proposed to patients suffering from a hereditary deficiency in antithrombin III.     

Hereditary deficit of antithrombin III

Antithrombin III is a well-known coagulation inhibitor. Its heterozygous deficit is demonstrated through concentrations reduced about by 50 p. 100. On a clinical level, about 40 p. 100 to 70 p. 100 patients present with deep venous thrombosis (visceral on the whole) and pulmonary embolisms from puberty. There are both qualitative and quantitative deficits, these appearing to be mostly frequent. Only calculation of activity in the presence of heparin (co-factor of heparin) enables to diagnose these two types of deficits. Treatment performed includes both AT III concentrated agents and heparin in severe cases. Recurrences prevention is performed thanks to antivitamins K. If surgical treatment or delivery, a prevention of any incidents thanks to a vicarious therapy (AT III concentrated agent) is to be used.